Although the clinical consequences of T. pallidum infection on the central nervous system have been appreciated for centuries, the pathogenesis and host response to CNS syphilis are poorly understood. Treponema pallidum invades the central nervous system (CNS) in the first weeks of infection, as demonstrated by CSF pleocytosis, elevated protein, reactive CSF-VDRL or identification of the organism. While most individuals resolve their CSF abnormalities over time, approximately 25% fail to do so and are at risk for development of clinical neurosyphilis. The issues regarding pathogenesis and treatment of CNS syphilis have been re-emphasized in recent years for two reasons: 1) Syphilis is epidemic in the United States. In 1990, the number of reported cases of infectious syphilis was higher than in any of the preceding 40 years, and an estimated 1.5 million persons in this country are infected with syphilis. 2) Recent case reports suggest that coinfection with HIV may increase the likelihood of development of neurosyphilis, even after standard therapy for early infection. We have recently developed a rabbit model of early neurosyphilis. This model parallels early CNS syphilis in humans in that intracisternally infected rabbits consistently develop a mononuclear CSF pleocytosis and have demonstrable T. pallidum in CSF and brain tissue; syphilitic uveitis is seen with same frequency in rabbits as in patients with early syphilis. We propose to use this model to 1) define the pathological and clinical consequences of CNS T. pallidum infection; 2) investigate the mechanisms of pathogenesis of CNS syphilis with respect to antigen specificity if infiltrating cells in the CSF, production and specificity of CSF antibodies, and inflammatory mediators; 3) examine the specificities and functions of antibodies and T lymphocytes in the clearance of organisms from the CNS; 4) determine the alterations in disease progression and host response in pharmacologically immunosuppressed rabbits; and 5) evaluate the efficacy of recommended therapies for early syphilis and neurosyphilis in immunocompetent and pharmacologically immunodeficient rabbits. The information gained from the proposed studies will be directly applicable to questions regarding the pathogenesis, immune response and treatment of CNS syphilis in humans, and to the interaction between syphilis infection and HIV.